PPIscreenML: Structure-based screening for protein-protein interactions using AlphaFold.

Protein-protein interactions underlie nearly all cellular processes. With the advent of protein structure prediction methods such as AlphaFold2 (AF2), models of specific protein pairs can be built extremely accurately in most cases. However, determining the relevance of a given protein pair remains an open question. It is presently unclear how to use best structure-based tools to infer whether a pair of candidate proteins indeed interact with one another: ideally, one might even use such information to screen amongst candidate pairings to build up protein interaction networks. Whereas methods for evaluating quality of modeled protein complexes have been co-opted for determining which pairings interact (e.g., pDockQ and iPTM), there have been no rigorously benchmarked methods for this task. Here we introduce PPIscreenML, a classification model trained to distinguish AF2 models of interacting protein pairs from AF2 models of compelling decoy pairings. We find that PPIscreenML out-performs methods such as pDockQ and iPTM for this task, and further that PPIscreenML exhibits impressive performance when identifying which ligand/receptor pairings engage one another across the structurally conserved tumor necrosis factor superfamily (TNFSF). Analysis of benchmark results using complexes not seen in PPIscreenML development strongly suggest that the model generalizes beyond training data, making it broadly applicable for identifying new protein complexes based on structural models built with AF2.

Secreted folate receptor γ drives fibrogenesis in metabolic dysfunction-associated steatohepatitis by amplifying TGFß signaling in hepatic stellate cells.

Hepatic fibrosis is the primary determinant of mortality in patients with metabolic dysfunction-associated steatohepatitis (MASH). Transforming growth factor-ß (TGFß), a master profibrogenic cytokine, is a promising therapeutic target that has not yet been translated into an effective therapy in part because of liabilities associated with systemic TGFß antagonism. We have identified that soluble folate receptor γ (FOLR3), which is expressed in humans but not in rodents, is a secreted protein that is elevated in the livers of patients with MASH but not in those with metabolic dysfunction-associated steatotic liver disease, those with type II diabetes, or healthy individuals. Global proteomics showed that FOLR3 was the most highly significant MASH-specific protein and was positively correlated with increasing fibrosis stage, consistent with stimulation of activated hepatic stellate cells (HSCs), which are the key fibrogenic cells in the liver. Exposure of HSCs to exogenous FOLR3 led to elevated extracellular matrix (ECM) protein production, an effect synergistically potentiated by TGFß1. We found that FOLR3 interacts with the serine protease HTRA1, a known regulator of TGFBR, and activates TGFß signaling. Administration of human FOLR3 to mice induced severe bridging fibrosis and an ECM pattern resembling human MASH. Our study thus uncovers a role of FOLR3 in enhancing fibrosis.

Risk Factors Associated with the Clinical Outcomes of COVID-19 and Its Variants in the Context of Cytokine Storm and Therapeutics/Vaccine Development Challenges.

The recent appearance of SARS-CoV-2 is responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic and has brought to light the importance of understanding this highly pathogenic agent to prevent future pandemics. This virus is from the same single-stranded positive-sense RNA family, Coronaviridae, as two other epidemic-causing viruses, SARS-CoV-1 and MERS-CoV. During this pandemic, one crucial focus highlighted by WHO has been to understand the risk factors that may contribute to disease severity and predict COVID-19 outcomes. In doing so, it is imperative to understand the virology of SARS-CoV-2 and the immunological response eliciting the clinical manifestation and progression of COVID-19. In this review, we provide clinical data-based analyses of how multiple risk factors (such as sex, race, HLA genotypes, blood groups, vitamin D deficiency, obesity, smoking, and asthma) contribute to the inflammatory overactivation and cytokine storm (frequently seen in COVID-19 patients) with a focus on the IL-6 pathway. We also draw comparisons to the virulence and pathophysiology of SARS and MERS to establish parallels in immune response and discuss the potential for therapeutic approaches that may limit disease progression in patients with higher risk profiles than others. Moreover, we cover the latest information on approved or upcoming COVID-19 vaccines. This paper also provides perspective on emerging variants and associated opportunistic infections such as black molds and fungus that have added to mortality in some parts of the world, such as India. This compilation of existing COVID-19 studies and data will provide an excellent referencing tool for the research, clinical, and public health communities.